The mechanisms by which hyperglycemia and dyslipidemia contribute to diabetic retinopathy (DR) pathology remain largely undefined. However, considerable experimental evidence points to the involvement of a group of pro-inflammatory cytokines. During early stages of non-proliferative diabetic retinopathy (NPDR), increased retinal levels of these inflammatory mediators (e.g., TNF?, IL-1?, IL-6, IL-8) are observed before visible signs of retinal vascular pathology. In animal models of DR, these up-regulated cytokines have been shown to elicit inflammatory responses from retinal vascular cells, evidenced by increased expression of adhesion proteins by endothelium (e.g., VCAM-1, ICAM-1, E-selectin) and apoptosis markers by pericytes (e.g., caspase-3, Annexin-V). These responses promote retinal vascular leukostasis and pericyte death, two hallmarks of NPDR. Recently, two families of endogenous epoxygenated lipids, the epoxyeicosatrienoic acids (EETs) and epoxydocosapentaenoic acids (EDPs), have been shown to inhibit production of soluble pro-inflammatory mediators, as well as pro-inflammatory and pro-apoptotic responses to these mediators, in a variety of cell types. EETs and EDPs are the products of arachidonic acid and docosahexaenoic acid metabolism, respectively, by cytochrome P450 (CYP) epoxygenase enzymes. Through their inhibitory actions on cytokine production and pro-inflammatory signaling pathways, EETs and EDPs exhibit potent anti- inflammatory properties before being hydrolyzed by soluble epoxide hydrolase (sEH) to diol products, which are much less biologically active. It is widely reported from studies in non-ocular tissues, that a number of diabetes-relevant stimuli cause down-regulation of EET/EDP-producing CYP enzymes and up-regulation of sEH, thus lowering tissue EET/EDP levels and mitigating their anti-inflammatory activities. Both the EET/EDP- producing CYP enzymes and the EET/EDP-degrading sEH enzyme are expressed in the retina and are localized to capillary endothelial cells, mural cells and Mller glia. Given ths background, and based on our own preliminary findings, we hypothesize the following: Under non-diabetic conditions, when retinal CYP and sEH expression levels are normal, EETs and EDPs block cytokine production by glial and vascular cells. Under diabetic conditions, CYP-dependent EET/EDP production is reduced, while sEH-dependent EET/EDP degradation is increased, resulting in lowered retinal EET/EDP levels and increased cytokine production. We hypothesize that by therapeutically elevating EET/EDP levels we will restore the normal EET/EDP balance, and block cytokine production and related downstream pathogenic events. We propose to test this hypothesis using both pharmacologic and genetic manipulation of retinal EET and EDP levels in relevant retinal cells and in an animal model of DR. While this is a completely novel therapeutic strategy for inhibiting DR pathology, we believe it is strongly supported by the literature and our own preliminary data.